Consumer medicine information

Cozaar

Losartan potassium

BRAND INFORMATION

Brand name

Cozaar

Active ingredient

Losartan potassium

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Cozaar.

What is in this leaflet

This leaflet answers some common questions about COZAAR. It does not contain all the available information. It does not take the place of talking to your doctor or pharmacist.

All medicines have risks and benefits. Your doctor has weighed the risks of you taking COZAAR against the benefits they expect it will have for you.

If you have any concerns about taking this medicine, ask your doctor or pharmacist.

Keep this leaflet with the medicine. You may need to read it again.

What COZAAR is used for

COZAAR lowers high blood pressure, which doctors call hypertension.

COZAAR is also used to slow the progression of kidney disease in people who have type 2 diabetes mellitus (also known as non-insulin dependent diabetes) with protein in their urine (which doctors call proteinuria).

Hypertension:
Everyone has blood pressure. This pressure helps get your blood all around your body. Your blood pressure may be different at different times of the day, depending on how busy or worried you are. You have hypertension (high blood pressure) when your blood pressure stays high, even when you are calm and relaxed.

There are usually no symptoms of hypertension. The only way of knowing that you have hypertension is to have your blood pressure checked on a regular basis. If high blood pressure is not treated it can lead to serious health problems. You may feel fine and have no symptoms, but eventually hypertension can cause stroke, heart disease or kidney failure. COZAAR helps to lower your blood pressure.

Type 2 Diabetes Mellitus:
Type 2 diabetes mellitus is a condition in which the body's cells do not respond to the effects of insulin or too little insulin is produced, resulting in an elevated blood (sugar) level, known as hyperglycaemia.

Insulin maintains the appropriate level of glucose in the blood by transporting it into the body's cells so that they can produce energy or store glucose until it's needed.

Hyperglycaemia can lead to serious problems with your heart, eyes, circulation or kidneys. When kidney damage occurs, its ability to filter blood is reduced, and proteins in the blood are lost in the urine. This may eventually lead to kidney failure. In people who have type 2 diabetes mellitus with protein in their urine, COZAAR helps to slow the worsening of kidney disease and reduce the need for dialysis or kidney transplantation.

How it works

COZAAR belongs to a group of medicines, called angiotensin II receptor antagonists. It works to lower your blood pressure by relaxing your blood vessels. In addition, COZAAR slows the progression of kidney disease in people who have type 2 diabetes mellitus with protein in the urine.

COZAAR is not addictive.

Before you take COZAAR

When you must not take it

Do not take COZAAR if:

  • you are pregnant or breast-feeding
    The use of COZAAR while you are pregnant or breast-feeding is not recommended. Your baby may absorb this medicine in the womb. COZAAR can cause harm or death to an unborn baby. Talk to your doctor about other ways to lower your blood pressure if you plan to become pregnant. If you get pregnant while taking COZAAR tell your doctor right away. It is not known whether COZAAR passes into breast milk, therefore it is not recommended to be taken while you are breast-feeding.
  • you have an allergy to COZAAR or any of the ingredients listed at the end of this leaflet
  • you have diabetes and are taking a medicine called aliskiren to reduce blood pressure.
  • the packaging is torn or shows signs of tampering
  • the expiry date on the pack has passed.
    If you take this medicine after the expiry date has passed, it may not work.

If you are not sure whether you should start taking COZAAR, talk to your doctor.

Do not give COZAAR to a child. There is no experience with the use of COZAAR in children.

Before you start to take it

Tell your doctor if:

  1. you intend to become pregnant or plan to breast-feed
    COZAAR should not be used during pregnancy or while breast-feeding.
  2. you are taking other medicines that may increase serum potassium (see Taking other medicines).
  3. you have any medical conditions, especially the following:
  • kidney disease
  • liver problems or have had these in the past.
  1. you have recently had excessive vomiting or diarrhoea
  2. you have any allergies to any other medicines or any other substances, such as foods, preservatives or dyes.

If you have not told your doctor about any of the above, tell them before you take any COZAAR.

Taking other medicines

Tell your doctor if you are taking any other medicines, including medicines that you buy without a prescription from your pharmacy, supermarket or health food shop.

Some medicines and COZAAR may interfere with each other. These include:

  • Other blood pressure medicines
  • diuretic tablets, also called fluid or water tablets, including potassium-sparing diuretics
  • potassium tablets
  • potassium-containing salt substitutes
  • other medicines that may increase serum potassium (e.g., trimethoprim-containing products).
  • medicines used to relieve pain, swelling, and other symptoms of inflammation, for example, indomethacin.
  • lithium (a medicine used to treat mood swings and some types of depressions)

These medicines may have an additive effect with COZAAR in lowering your blood pressure, or may affect how well it works, or may lead to increases in potassium in your blood. You may need to take different amounts of your medicine, or you may need to take different medicines.

Your doctor or pharmacist has more information on medicines to be careful with or avoid while taking COZAAR.

How to take COZAAR

How much to take

Your doctor will tell you how many tablets you need to take each day. This depends on your condition and whether you are taking other medicines. Take COZAAR only when prescribed by your doctor.

For high blood pressure:
For most patients, the usual starting dose is one 50 mg tablet taken once a day. Some patients may need a lower starting dose. The dose may need to be increased depending on your blood pressure. Most patients take between 25 to 100 mg each day, taken as a single dose or in divided doses.

For type 2 diabetes mellitus with protein in the urine:
The usual starting dose is one 50 mg tablet taken once a day. The dose may be increased to 100 mg once a day depending on your blood pressure.

Follow all directions given to you by your doctor carefully. They may differ from the information contained in this leaflet.

If you do not understand the instructions on the box, ask your doctor or pharmacist for help.

When to take it

Take your COZAAR at about the same time each day. Taking your tablet(s) at the same time each day will have the best effect. It will also help you remember when to take the tablets.

Swallow COZAAR with a glass of water.

It does not matter whether you take COZAAR before or after food.

How long to take it

COZAAR helps control your high blood pressure, but does not cure it. Therefore COZAAR must be taken every day. Continue taking COZAAR for as long as your doctor prescribes.

If you forget to take it

If it is almost time for your next dose, skip the dose you missed and take your next dose when you are meant to. Otherwise, take it as soon as you remember, and then go back to taking your tablet(s) as you would normally.

If you are not sure whether to skip the dose, talk to your doctor or pharmacist.

Do not take a double dose to make up for the dose that you missed.

If you have trouble remembering to take your tablets, ask your pharmacist for some hints.

If you take too much (overdose)

Immediately telephone your doctor or Poisons Information Centre (telephone 13 11 26), or go to accident and emergency at your nearest hospital, if you think that you or anyone else may have taken too much COZAAR. Do this even if there are no signs of discomfort or poisoning.

If you take too many tablets, you will probably feel light-headed or dizzy.

While you are using COZAAR

Things you must do

If you become pregnant while taking COZAAR, tell your doctor immediately. Your doctor needs to know immediately so that COZAAR can be replaced by another medicine.

Have your blood pressure checked when your doctor says, to make sure COZAAR is working.

If you are about to be started on any new medicine, tell your doctor and pharmacist that you are taking COZAAR.

If you feel light-headed, dizzy or faint, get up slowly when getting out of bed or standing up. You may feel light-headed or dizzy while taking COZAAR, especially if you are also taking a diuretic (fluid tablet). This may become worse if you stand up quickly as your blood pressure may fall. Standing up slowly, especially when you get up from bed or chairs, will help your body get used to the change in position and blood pressure. This problem is not common. If it occurs and gets worse or continues, talk to your doctor.

If you plan to have surgery (even at the dentist) that needs a general anaesthetic, tell your doctor or dentist that you are taking COZAAR.

Make sure you drink enough water during exercise and hot weather when you are taking COZAAR, especially if you sweat a lot. If you do not drink enough water while taking COZAAR, you may faint or feel light-headed or sick. This is because your body doesn't have enough fluid and your blood pressure is low. If you continue to feel unwell, tell your doctor.

If you have excessive vomiting and/or diarrhoea while taking COZAAR, tell your doctor. This can also mean that you are losing too much water and your blood pressure may become too low.

If your doctor has prescribed potassium tablets for you, continue taking them. COZAAR contains a very small amount of potassium, but this does not replace any potassium tablets that you may be taking.

Go to your doctor regularly for a check-up. Your doctor may occasionally do a blood test to check your potassium level in the blood and to see how your kidneys are working.

Things you must not do

Do not give COZAAR to anyone else, even if they have the same condition as you.

Things to be careful of

Be careful driving or operating machinery until you know how COZAAR affects you. As with many other medicines used to treat high blood pressure, COZAAR may cause dizziness or light-headedness in some people. Make sure you know how you react to COZAAR before you drive a car, operate machinery, or do anything else that could be dangerous if you are dizzy or light-headed. If you drink alcohol, dizziness or light-headedness may be worse.

Things that would be helpful for your blood pressure

Some self-help measures suggested below may help your condition. Talk to your doctor or pharmacist about these measures and for more information.

  • Alcohol -
    your doctor may advise you to limit your alcohol intake.
  • Diet -
    eat a healthy diet which includes plenty of fresh vegetables, fruit, bread, cereals and fish. Also eat less fat and sugar.
  • Exercise -
    regular exercise helps to reduce blood pressure and helps the heart get fitter, but it is important not to overdo it. Walking is good exercise, but try to find a route that is fairly flat. Before starting any exercise, ask your doctor about the best kind of programme for you.
  • Salt -
    your doctor may advise you to watch the amount of salt in your diet. To reduce your salt intake you should avoid using salt in cooking or at the table.
  • Smoking -
    your doctor may advise you to stop smoking or at least cut down.
  • Weight -
    your doctor may suggest losing some weight to help lower your blood pressure and help lessen the amount of work your heart has to do. Some people may need a dietician's help to lose weight.

Side Effects

Tell your doctor or pharmacist as soon as possible if you do not feel well while you are taking COZAAR.

COZAAR helps most people with high blood pressure, but it may have unwanted side effects in a few people. All medicines can have side effects. Sometimes they are serious, most of the time they are not. You may need medical treatment if you get some of the side effects.

Ask your doctor or pharmacist to answer any questions you may have.

Tell your doctor if you notice any of the following and they worry you:

  • dizziness
  • lightheadedness
  • tiredness or weakness
  • spinning sensation
  • generally feeling unwell
  • increased sensitivity of the skin to sun
  • inability to get or maintain an erection

These are the common side effects of COZAAR. For the most part these have been mild.

Also, tell your doctor if you develop cough.

Tell your doctor immediately if you notice any of the following:

  • skin rash, itchiness
  • aching muscles, not caused by exercise
  • signs of anaemia, such as tiredness, being short of breath, and looking pale
  • bleeding or bruising more easily than normal

These may be serious side effects. Skin rash and itchiness may be symptoms of an allergic reaction. You may need medical attention. These side effects are not common.

If any of the following happen, stop taking COZAAR and tell your doctor immediately or go to accident and emergency at your nearest hospital:

  • swelling of the face, lips, mouth, tongue or throat which may cause difficulty in swallowing or breathing
  • severe and sudden onset of pinkish, itchy swellings on the skin, also called hives or nettlerash

These are serious side effects. If you have them, you may have had a serious allergic reaction to COZAAR. You may need urgent medical attention or hospitalisation. These side effects are rare.

Other side effects not listed above may also occur in some patients. Tell your doctor if you notice any other effects.

Do not be alarmed by this list of possible side effects. You may not experience any of them.

After using COZAAR

Storage

Keep your tablets in the blister pack until it is time to take them. If you take the tablets out the blister pack they may not keep well.

Keep it in a cool dry place where the temperature stays below 30°C. Do not store it or any other medicine in the bathroom or near a sink.

Do not leave it in the car or on window sills. Heat and dampness can destroy some medicines.

Keep it where children cannot reach it. A locked cupboard at least one-and-a-half metres above the ground is a good place to store medicines.

Disposal

If your doctor tells you to stop taking COZAAR or the tablets have passed their expiry date, ask your pharmacist what to do with any that are left over.

Product description

What it looks like

COZAAR comes in one type of tablet:

  • COZAAR 50 mg - white, oval shaped tablet with "952" marked on one side and scored on the other side.

A pack of COZAAR contains 30 tablets.

Ingredients

Active ingredient:

  • COZAAR 50 mg - losartan potassium 50 mg per tablet

Inactive ingredients:

  • microcrystalline cellulose
  • lactose monohydrate
  • pregelatinised maize starch
  • magnesium stearate
  • hyprolose
  • hypromellose
  • titanium dioxide
  • carnauba wax

COZAAR does not contain gluten, sucrose, tartrazine or any other azo dyes.

Supplier

COZAAR is supplied in Australia by:

Organon Pharma Pty Limited
Building A, 26 Talavera Road,
Macquarie Park, NSW 2113 Australia

This leaflet was prepared in February 2021.

Australian Register Number:

50 mg - AUST R 54809

Copyright © 2018 Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Whitehouse Station, NJ, USA. All Rights Reserved.

S-WPPI-MK0954-T-032018

Published by MIMS April 2021

BRAND INFORMATION

Brand name

Cozaar

Active ingredient

Losartan potassium

Schedule

S4

 

1 Name of Medicine

Losartan potassium.

2 Qualitative and Quantitative Composition

Cozaar (losartan potassium) 50 mg tablets.
Losartan potassium is a white to off-white free-flowing crystalline powder. It is freely soluble in water, soluble in alcohols, and slightly soluble in common organic solvents, such as acetonitrile and methyl ethyl ketone.

List of excipients with known effect.

Lactose monohydrate.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Cozaar (losartan potassium) 50 mg tablet: White, oval scored tablet, marked "952".

4 Clinical Particulars

4.1 Therapeutic Indications

Hypertension.

Cozaar is indicated for the treatment of hypertension.
It may be used alone or in combination with other antihypertensive agents (e.g. thiazide diuretics).

Renal protection in type 2 diabetic patients with proteinuria.

Cozaar is indicated to delay the progression of renal disease in hypertensive type 2 diabetics with proteinuria, defined as urinary albumin to creatinine ratio ≥ 300 mg/g.

4.2 Dose and Method of Administration

The usual starting and maintenance dose is 50 mg once daily for most patients. The maximal antihypertensive effect is attained 3-6 weeks after initiation of therapy.
If the antihypertensive effect using 50 mg once daily is inadequate, 25 mg twice daily is recommended prior to increasing the dose.
For patients with intravascular volume-depletion (e.g. those treated with high-dose diuretics), a starting dose of 25 mg once daily should be considered (see Section 4.4 Special Warnings and Precautions for Use).
Cozaar can be administered once or twice daily. The total daily dose ranges from 25 mg to 100 mg.
No initial dosage adjustment is necessary for elderly patients or for patients with renal impairment, including patients on dialysis. A lower dose should be considered for patients with a history of hepatic impairment (see Section 4.4 Special Warnings and Precautions for Use).
Cozaar may be administered with other antihypertensive agents.
Cozaar may be administered with or without food.

4.3 Contraindications

Cozaar is contraindicated in pregnant women and in patients who are hypersensitive to any component of this product.
Cozaar should not be administered with aliskiren in patients with diabetes (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

4.4 Special Warnings and Precautions for Use

Foetal toxicity.

Use of drugs that act on the renin-angiotensin system during the second and third trimesters of pregnancy reduces foetal renal function and increases foetal and neonatal morbidity and death. Resulting oligohydramnios can be associated with foetal lung hypoplasia and skeletal deformations. Potential neonatal adverse effects include skull hypoplasia, anuria, hypotension, renal failure, and death. When pregnancy is detected, discontinue Cozaar as soon as possible. See Section 4.6 Fertility, Pregnancy and Lactation, Use in pregnancy.

Hypersensitivity.

Angioedema (see Section 4.8 Adverse Effects (Undesirable Effects)).

Hypotension and electrolyte/fluid imbalance.

In patients who are intravascularly volume-depleted (e.g. those treated with high-dose diuretics), symptomatic hypotension may occur. These conditions should be corrected prior to administration of Cozaar, or a lower starting dose should be used (see Section 4.2 Dose and Method of Administration).
Electrolyte imbalances are common in patients with renal impairment, with or without diabetes, and should be addressed. In a clinical study conducted in type 2 diabetic patients with proteinuria, the incidence of hyperkalaemia was higher in the group treated with Cozaar as compared to the placebo group; however, few patients discontinued therapy due to hyperkalemia (see Section 4.8 Adverse Effects (Undesirable Effects), Laboratory test findings).
Concomitant use of other drugs that may increase serum potassium may lead to hyperkalaemia (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

Use in hepatic impairment.

Based on pharmacokinetic data which demonstrate significantly increased plasma concentrations of losartan in cirrhotic patients, a lower dose should be considered for patients with a history of hepatic impairment (see Section 4.2 Dose and Method of Administration; Section 5.2 Pharmacokinetic Properties).

Use in renal impairment.

As a consequence of inhibiting the renin-angiotensin-aldosterone system, changes in renal function including renal failure have been reported in susceptible individuals. In patients whose renal function may depend on the activity of the renin-aldosterone system (e.g. patients with severe congestive heart failure), treatment with angiotensin converting enzyme inhibitors has been associated with oliguria and/or progressive azotemia and (rarely) with acute renal failure and/or death. Angiotensin II receptor antagonists would be expected to behave similarly.
Other drugs that affect the renin-angiotensin system may increase blood urea and serum creatinine in patients with bilateral renal artery stenosis or stenosis of the artery to a solitary kidney. Similar effects have been reported with Cozaar.

Use in the elderly.

In clinical studies there was no age-related difference in the efficacy or safety profile of losartan.

Paediatric use.

Safety and effectiveness in children have not been established.

Effects on laboratory tests.

See Section 4.8 Adverse Effects (Undesirable Effects), Laboratory test findings.

4.5 Interactions with Other Medicines and Other Forms of Interactions

No drug interactions of clinical significance have been identified. Compounds which have been studied in clinical pharmacokinetic trials include digoxin, warfarin, cimetidine and phenobarbitone and ketoconazole. Rifampicin and fluconazole have been reported to reduce levels of active metabolite. Clinical studies have shown that concomitant use of losartan and hydrochlorothiazide may lead to potentiation of the antihypertensive effects.
As with other drugs that block angiotensin II or its effect, concomitant use of potassium-sparing diuretics (e.g. spironolactone, triamterene, amiloride), potassium supplements, salt substitutes containing potassium, or other drugs that may increase serum potassium (e.g. trimethoprim-containing products) may lead to increases in serum potassium.
As with other drugs which affect the excretion of sodium, lithium excretion may be reduced. Therefore, serum lithium levels should be monitored carefully if lithium salts are to be co-administered with angiotensin II receptor antagonists.
The antihypertensive effect of losartan may be attenuated by the non-steroidal anti-inflammatory drug indomethacin.
Non-steroidal anti-inflammatory drugs (NSAIDs) including selective cyclooxygenase-2 inhibitors (COX-2 inhibitors) may reduce the effect of diuretics and other antihypertensive drugs. Therefore, the antihypertensive effect of angiotensin II receptor antagonists or ACE inhibitors may be attenuated by NSAIDs including selective COX-2 inhibitors.
In some patients with compromised renal function (e.g. elderly patients or patients who are volume-depleted, including those on diuretic therapy) who are being treated with non-steroidal anti-inflammatory drugs, including selective cyclooxygenase-2 inhibitors, the co-administration of angiotensin II receptor antagonists or ACE inhibitors may result in a further deterioration of renal function including possible acute renal failure which is usually reversible. Therefore, the combination should be administered with caution in patients with compromised renal function.
These interactions should be considered in patients taking NSAIDs including selective COX-2 inhibitors concomitantly with diuretics and angiotensin II antagonists. Therefore, the combination should be administered with caution, especially in the elderly.

Combination use of ACE inhibitors or angiotensin receptor antagonists, anti-inflammatory drugs and thiazide diuretics.

The use of an ACE inhibiting drug (ACE-inhibitor or angiotensin receptor antagonist), an anti-inflammatory drug (NSAID or COX-2 inhibitor) and a thiazide diuretic at the same time increases the risk of renal impairment. This includes use in fixed-combination products containing more than one class of drug. Combined use of these medications should be accompanied by increased monitoring of serum creatinine, particularly at the institution of the combination. The combination of drugs from these three classes should be used with caution particularly in elderly patients or those with pre-existing renal impairment.
Dual blockade of the renin-angiotensin-aldosterone system (RAAS) with angiotensin receptor blockers, ACE inhibitors, or aliskiren is associated with increased risks of hypotension, syncope, hyperkalemia, and changes in renal function (including acute renal failure) compared to monotherapy. Closely monitor blood pressure, renal function, and electrolytes in patients on Cozaar and other agents that affect the RAAS. Do not co-administer aliskiren with Cozaar in patients with diabetes. Avoid use of aliskiren with Cozaar in patients with renal impairment (GFR < 60 mL/min).

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

Repeat-dose studies in animals did not show any evidence of toxic effect on the reproductive system, and no adverse effects on fertility were observed in male or female rats at oral doses of losartan potassium up to 150-200 mg/kg/day.
(Category D)
Drugs that act directly on the renin-angiotensin system can cause injury, and death to the developing foetus when administered to pregnant women. Several dozen cases have been reported in the world literature in patients who were taking angiotensin converting enzyme inhibitors. When pregnancy is detected, discontinue Cozaar as soon as possible.
The use of drugs that act directly on the renin-angiotensin system during the second and third trimesters of pregnancy reduces foetal renal function and increases foetal and neonatal morbidity and death. Potential neonatal adverse effects include hypotension, neonatal skull hypoplasia, anuria, reversible or irreversible renal failure, and death. Oligohydramnios has also been reported, presumably resulting from decreased foetal renal function; oligohydramnios in this setting has been associated with skeletal deformations, foetal limb contractures, craniofacial deformation, foetal lung hypoplasia and hypoplastic lung development. Prematurity, intrauterine growth retardation and patent ductus arteriosus have also been reported, although it is not clear whether these occurrences were due to exposure to the drug. When pregnancy is detected, discontinue Cozaar as soon as possible.
These adverse effects do not appear to have resulted from intrauterine drug exposure that has been limited to the first trimester. Mothers whose embryos and foetuses are exposed to an angiotensin II receptor antagonist only during the first trimester should be so informed. Nonetheless, when patients become pregnant, physicians should have the patient discontinue the use of Cozaar as soon as possible.
These adverse outcomes are usually associated with the use of these drugs in the second and third trimesters of pregnancy. Most epidemiologic studies examining foetal abnormalities after exposure to antihypertensive use in the first trimester have not distinguished drugs affecting the renin-angiotensin system from other antihypertensive agents. Appropriate management of maternal hypertension during pregnancy is important to optimize outcomes for both mother and foetus. Although there is no experience with the use of Cozaar in pregnant women, animal studies with losartan potassium have demonstrated foetal and neonatal injury and death, the mechanism of which is believed to be pharmacologically mediated through effects on the renin-angiotensin system. In humans, foetal renal perfusion, which is dependent upon the development of the renin angiotensin system, begins in the second trimester; thus, risk to the foetus increases if Cozaar is administered during the second or third trimesters of pregnancy.

Neonates with a history of in utero exposure to Cozaar.

Infants with histories of in utero exposure to an angiotensin II receptor antagonist should be closely observed for hypotension, oliguria and hyperkalaemia.
If oliguria or hypotension occur, direct attention toward support of blood pressure and renal perfusion. Exchange transfusions or dialysis may be required as a means of reversing hypotension and/or substituting for disordered renal function.
It is not known whether losartan is excreted in human milk, but studies in rats indicate that both losartan and its active carboxylic acid metabolite are excreted in milk. Many drugs are excreted in human milk and because of the potential for adverse effects on the nursing infant, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.

4.7 Effects on Ability to Drive and Use Machines

There are no data to suggest that Cozaar affects the ability to drive and use machines. When driving vehicles or operating machines it should be taken into account that occasionally dizziness or weariness may occur (see Section 4.8 Adverse Effects (Undesirable Effects)).

4.8 Adverse Effects (Undesirable Effects)

Cozaar has been evaluated for safety in more than 3300 patients treated for essential hypertension and 4058 patients overall. Over 1200 patients were treated for over 6 months and more than 800 for over one year. In general, treatment with Cozaar was well tolerated. The overall incidence of adverse experiences reported with Cozaar was comparable to placebo. For the most part, adverse experiences have been mild and transient in nature and have not required discontinuation of therapy. In controlled clinical trials, discontinuation of therapy due to clinical adverse experiences was required in only 2.3% and 3.7% of patients treated with Cozaar and placebo, respectively.
In controlled clinical trials for essential hypertension, dizziness was the only adverse experience reported as drug-related that occurred with an incidence greater than placebo in one percent or more of patients treated with Cozaar. In addition, dose-related orthostatic effects were seen in less than one percent of patients. Rarely, rash was reported, although the incidence in controlled clinical trials was less than placebo.
Table 1 table of adverse events is based on four 6-12 week placebo controlled trials involving over 1000 patients on various doses (10-150 mg) of losartan and over 300 patients given placebo. All doses of losartan are grouped because none of the adverse events appeared to have a dose-related frequency. Table 1 includes all adverse events, whether or not attributed to the treatment, occurring in at least 1% of patients treated with losartan and that were more frequent on losartan than placebo.
The following adverse events were also reported at a rate of 1% or greater in patients treated with losartan, but were as, or more frequent, in the placebo group: asthenia/ fatigue, oedema/ swelling, abdominal pain, chest pain, nausea, headache, pharyngitis.
Adverse events occurred at about the same rates in men and women, older and younger patients, and black and non-black patients.
A patient with known hypersensitivity to aspirin and penicillin, when treated with Cozaar, was withdrawn from study due to swelling of the lips and eyelids and facial rash, reported as angioedema, which returned to normal 5 days after therapy was discontinued.
Superficial peeling of palms and haemolysis was reported in one subject.
In addition to the adverse events above, potentially important events that occurred in at least two patients/ subjects exposed to losartan or other adverse events that occurred in < 1% of patients in clinical studies are listed below. It cannot be determined whether these events were causally related to losartan:

Body as a whole.

Facial oedema, fever, orthostatic effects, syncope.

Cardiovascular.

Angina pectoris, second degree AV block, CVA, hypotension, myocardial infarction, arrhythmias including atrial fibrillation, palpitation, sinus bradycardia, tachycardia, ventricular tachycardia, ventricular fibrillation.

Digestive.

Anorexia, constipation, dental pain, dry mouth, flatulence, gastritis, vomiting.

Haematologic.

Anaemia.

Metabolic.

Gout.

Musculoskeletal.

Arm pain, hip pain, joint swelling, knee pain, musculoskeletal pain, shoulder pain, stiffness, arthralgia, arthritis, fibromyalgia, muscle weakness.

Nervous system/psychiatric.

Anxiety, anxiety disorder, ataxia, confusion, depression, dream abnormality, hypoaesthesia, decreased libido, memory impairment, migraine, nervousness, paraesthesia, peripheral neuropathy, panic disorder, sleep disorder, somnolence, tremor, vertigo.

Respiratory.

Dyspnoea, bronchitis, pharyngeal discomfort, epistaxis, rhinitis, respiratory congestion.

Skin.

Alopecia, dermatitis, dry skin, ecchymosis, erythema, flushing, photosensitivity, pruritus, rash, sweating, urticaria.

Special senses.

Blurred vision, burning/ stinging in the eye, conjunctivitis, taste perversion, tinnitus, decrease in visual acuity.

Urogenital.

Impotence, nocturia, urinary frequency, urinary tract infection.
The following adverse reactions have been reported in post-marketing experience:

Hypersensitivity.

Anaphylactic reactions, angioedema including swelling of the larynx and glottis causing airway obstruction and/or swelling of the face, lips, pharynx and/or tongue has been reported rarely in patients treated with losartan; some of these patients previously experienced angioedema with other drugs including ACE inhibitors. Vasculitis, including Henoch-Schoenlein purpura, has been reported rarely.

Gastrointestinal.

Hepatitis (reported rarely), diarrhoea, liver function abnormalities, vomiting.

General disorders and administration site conditions.

Malaise.

Haematologic.

Anaemia, thrombocytopenia (reported rarely).

Musculoskeletal.

Myalgia, arthralgia.
Rare cases of rhabdomyolysis have been reported in patients receiving angiotensin II receptor blockers.

Nervous system/psychiatric.

Migraine, dysgeusia.

Reproductive system and breast disorders.

Erectile dysfunction/impotence.

Respiratory.

Cough.

Skin.

Urticaria, pruritus, erythroderma, photosensitivity.

Laboratory test findings.

In controlled clinical trials, clinically important changes in standard laboratory parameters were rarely associated with administration of Cozaar.

Creatinine, blood urea nitrogen.

Minor increases in blood urea nitrogen (BUN) or serum creatinine were observed in less than 0.1 percent of patients with essential hypertension treated with Cozaar alone. No patient discontinued taking Cozaar alone due to increased BUN or serum creatinine (see Section 4.4 Special Warnings and Precautions for Use, Use in renal impairment).

Haemoglobin and haematocrit.

Small decreases in haemoglobin and haematocrit (mean decreases of approximately 0.11 grams percent and 0.09 volume percent respectively) occurred frequently in patients treated with Cozaar alone, but were rarely of clinical importance. No patients were discontinued due to anaemia.

Liver function tests.

Occasional elevations of liver enzymes and/or serum bilirubin have occurred. In patients with essential hypertension treated with Cozaar alone, one patient (< 0.1%) was discontinued due to these laboratory adverse experiences.

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions at www.tga.gov.au/reporting-problems.

4.9 Overdose

Limited data are available in regard to overdosage in humans. The most likely manifestation of overdosage would be hypotension and tachycardia; bradycardia could occur from parasympathetic (vagal) stimulation. If symptomatic hypotension should occur, supportive treatment should be instituted.
Neither losartan nor the active metabolite can be removed by haemodialysis. For information on the management of overdose, contact the Poisons Information Centre on 131126 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Cozaar (losartan potassium) is the first non-peptide orally active angiotensin II receptor (type AT1) antagonist to be used for the treatment of hypertension. Cozaar also provides a reduction in the risk of stroke in hypertensive patients with left ventricular hypertrophy and renal protection for type 2 diabetic patients with proteinuria.
Losartan is an oral angiotensin II receptor (type AT1) antagonist. Angiotensin II binds to the AT1 receptor found in many tissues (e.g. vascular smooth muscle, adrenal gland, kidneys and the heart) and elicits several important biological actions, including vasoconstriction and the release of aldosterone. Angiotensin II also stimulates smooth muscle cell proliferation. Based on binding and pharmacological bioassays, losartan binds selectively to the AT1 receptor. There is also an AT2 receptor found in many tissues. The functions of AT2 receptors have not been established. In vitro and in vivo, both losartan and its pharmacologically active carboxylic acid metabolite (E-3174) block all physiologically relevant actions of angiotensin II, regardless of the source or route of synthesis. The active metabolite is 10 to 40 times more potent by weight than losartan and appears to be a reversible, non-competitive inhibitor of the AT1 receptor.
During losartan administration, removal of angiotensin II negative feedback on renin secretion leads to increased plasma renin activity. Increases in plasma renin activity lead to increases in angiotensin II in plasma. Even with these increases, antihypertensive activity and suppression of plasma aldosterone concentration are maintained, indicating effective angiotensin II receptor blockade.
Losartan binds selectively to the AT1 receptor and does not bind to or block other hormone receptors or ion channels important in cardiovascular regulation. Furthermore, losartan does not inhibit ACE (kininase II), the enzyme that degrades bradykinin. Consequently, effects not directly related to blocking the AT1 receptor, such as the potentiation of bradykinin-mediated effects or the generation of oedema (losartan 1.7%, placebo 1.9%), are not associated with losartan.
Losartan has been shown to block responses to angiotensin I and angiotensin II without affecting responses to bradykinin, a finding which is consistent with the specific mechanism of action of losartan. In contrast, ACE inhibitors have been shown to block responses to angiotensin I and enhance responses to bradykinin without altering the response to angiotensin II, thus providing a pharmacodynamic distinction between losartan and ACE inhibitors.
In a study specifically designed to assess the incidence of cough in patients treated with Cozaar as compared to patients treated with ACE inhibitors, the incidence of cough reported by patients receiving Cozaar or hydrochlorothiazide was similar and was significantly less than in patients treated with an ACE inhibitor. In addition, in an overall analysis of 16 double-blind clinical trials in 4131 patients, the incidence of spontaneously reported cough in patients treated with Cozaar was similar (3.1%) to that of patients treated with placebo (2.6%) or hydrochlorothiazide (4.1%), whereas the incidence with ACE inhibitors was 8.8%.
In non diabetic hypertensive patients with proteinuria, the administration of losartan potassium significantly reduces proteinuria, fractional excretion of albumin and IgG. Losartan maintains glomerular filtration rate and reduces filtration fraction. The mechanism of action of the uricosuric effect of losartan studied in normotensive subjects appears to be independent of angiotensin II blockade. Generally, in clinical trials, losartan caused a decrease in serum uric acid (usually 0.4 mg/dL) which was persistent in chronic therapy.
Losartan has no effect on autonomic reflexes and no sustained effect on plasma noradrenaline.
Losartan potassium, administered in doses of up to 150 mg once daily, did not cause clinically important changes in fasting triglycerides, total cholesterol in patients with hypertension. The same doses of losartan had no effect on fasting glucose levels.
In patients with left ventricular failure, 25 mg and 50 mg doses of losartan produced positive haemodynamic and neurohormonal effects characterised by an increase in cardiac index and decreases in pulmonary capillary wedge pressure, systemic vascular resistance, mean systemic arterial pressure and heart rate and a reduction in circulating levels of aldosterone and noradrenaline. The occurrence of hypotension was dose related in these heart failure patients.
The antihypertensive efficacy of Cozaar was demonstrated in randomised, double-blind, placebo controlled and comparator studies over a 12 week period and in an open-label extension study for over 12 months.
Once-daily administration of Cozaar to patients with mild to moderate essential hypertension produced statistically significant reductions in systolic and diastolic blood pressure; the antihypertensive effect was maintained in clinical studies for up to one year. Measurement of blood pressure at trough (24 hours postdose) relative to peak (5-6 hours postdose) demonstrated relatively smooth blood pressure reduction over 24 hours. The antihypertensive effect paralleled the natural diurnal rhythms. Blood pressure reduction at the end of the dosing interval was approximately 70-80% of the effect seen 5-6 hours postdose. Discontinuation of losartan in hypertensive patients did not result in an abrupt rebound of blood pressure. Despite the significant decrease in blood pressure, administration of Cozaar has no clinically significant effect on heart rate. The mechanism involved in the lack of reflex tachycardia is not clearly established.
The antihypertensive effect of Cozaar 50 mg is similar to once-daily administration of enalapril 20 mg. The antihypertensive effect of once-daily administration of Cozaar 50-100 mg is comparable to once-daily administration of atenolol 50-100 mg. The effect of administration of Cozaar 50-100 mg once daily also is equivalent to felodipine extended-release 5-10 mg in older hypertensives (> 65 years) after 12 weeks of therapy.
Cozaar is equally effective in males and females and in younger (< 65 years) and older (> 65 years) hypertensives. Plasma concentrations of losartan were about twice as high in female hypertensives as male hypertensives, but concentrations of the active metabolite were similar in males and females. Although Cozaar is antihypertensive in all races, as with other drugs that affect the renin-angiotensin system, black hypertensive patients have a smaller average response to losartan monotherapy than non black patients. Pharmacokinetic differences due to race have not been studied.
When given together with thiazide-type diuretics, the blood pressure lowering effects of Cozaar are approximately additive.
Data are currently not available to assess the long-term beneficial effect on morbidity and mortality in patients taking angiotensin II receptor antagonists.

Clinical trials.

LIFE study.

The Losartan Intervention For Endpoint reduction in hypertension (LIFE) study was a large, multicenter, multinational, randomised, triple-blind, active-controlled study conducted in 9193 hypertensive patients aged 55 to 80 years (mean 67 years) with ECG-documented left ventricular hypertrophy. Of the patients enrolled at baseline, 1195 (13%) had diabetes; 1326 (14%), isolated systolic hypertension; 1468 (17%), coronary heart disease; and 728 (8%), cerebrovascular disease. The goal of the study was to demonstrate the cardiovascular protective effects of Cozaar versus atenolol, over and above the benefits of blood pressure control alone (blood pressure was measured at trough). To meet this objective, the study was designed to achieve equal blood pressure in both treatment groups. Patients were randomised to receive once daily Cozaar 50 mg or atenolol 50 mg. If goal blood pressure (< 140/90 mmHg) was not reached, hydrochlorothiazide (12.5 mg) was added first and, if needed, the dose of Cozaar or atenolol was then increased to 100 mg once daily. If necessary, other antihypertensive treatments (e.g. increase in dose of hydrochlorothiazide therapy to 25 mg or addition of other diuretic therapy, calcium channel blockers, alpha-blockers, or centrally acting agents, but not ACE inhibitors, angiotensin II antagonists, or beta-blockers) were added to the treatment regimen to reach the goal blood pressure.
In both treatment groups, blood pressure was significantly lowered to similar levels and a similar proportion of patients achieved goal blood pressure. The mean length of follow up was 4.8 years.
The primary endpoint was the composite of cardiovascular morbidity and mortality as measured by a reduction in the combined incidence of cardiovascular death, stroke and myocardial infarction. In this trial 5% of the patients treated with Cozaar suffered stroke compared to 7% of patients treated with atenolol, a reduction of 25% in the relative risk of stroke compared to atenolol (see Table 2). The effect of Cozaar on stroke appeared to be over and above its beneficial effects on blood pressure control alone. The rates of cardiovascular death and myocardial infarction were not significantly different between the treatment groups. Although the results showed that treatment with Cozaar resulted in a 13% risk reduction as compared with atenolol for patients reaching the primary composite endpoint, this effect was largely driven by a reduction in the risk on stroke.
The difference in the incidence of stroke in patients treated with Cozaar and atenolol amounts to 1 additional stroke prevented for every 53 patients treated with Cozaar for 5 years. The reduction in the incidence of stroke does not replace the need to adequately titrate patients to adequate blood pressure control.
The effects of Cozaar versus atenolol on cardiovascular morbidity and mortality were examined in subgroups of patients with a baseline history of diabetes mellitus (n=1195) or isolated systolic hypertension (ISH) (n=1326). For the primary composite endpoint, the results seen in these subgroups were consistent with the benefit of therapy with Cozaar seen in the overall study population: in diabetic patients, a 24% risk reduction (p=0.03) was observed and in patients with isolated systolic hypertension, a 25% risk reduction (p=0.06) was observed (see Table 3). Consistent with the results seen in the overall population, a reduction in stroke was an important contributor to the benefit observed in patients with diabetes or ISH.

Race.

Based on the LIFE study, the benefits of Cozaar on cardiovascular morbidity and mortality compared to atenolol do not apply to black patients with hypertension and left ventricular hypertrophy although both treatment regimens effectively lowered blood pressure in black patients. In the LIFE study, Cozaar decreased the risk of cardiovascular morbidity and mortality compared to atenolol in non-black, hypertensive patients with left ventricular hypertrophy (n=8660) as measured by the primary endpoint of the combined incidence of cardiovascular death, stroke and myocardial infarction (p=0.003). In this study, however, black patients treated with atenolol were at lower risk of experiencing the primary composite endpoint compared with black patients treated with Cozaar (p=0.03). In the subgroup of black patients (n=533; 6% of the LIFE study patients), there were 29 primary endpoints among 263 patients on atenolol (11%, 25.9 per 1000 patient years) and 46 primary endpoints among 270 patients (17%, 41.8 per 1000 patient years) on Cozaar.

RENAAL study.

The Reduction of Endpoints in NIDDM with the Angiotensin II Receptor Antagonist Losartan (RENAAL) study was a large, multicenter, randomised, placebo-controlled, double-blind study conducted world-wide in 1513 type 2 diabetic patients with proteinuria1 (751 treated with Cozaar), with or without hypertension. The goal of the study was to demonstrate the renal protective effects of Cozaar over and above the benefits of blood pressure control alone. To meet this objective the study was designed to achieve equal blood pressure control in both treatment groups. Patients with proteinuria and serum creatinine of 1.3-3.0 mg/dL2 (115-265 micromol/L) were randomised to receive Cozaar 50 mg once daily titrated according to blood pressure response, or placebo, on a background of conventional antihypertensive therapy excluding ACE inhibitors and angiotensin II antagonists. Investigators were instructed to titrate study drug to 100 mg once daily as appropriate; 72% of patients were taking the 100 mg daily dose the majority of the time they were on study drug. Other antihypertensive agents (diuretics, calcium-channel blockers, alpha- or beta-blockers, and centrally acting agents) could be added as needed in both groups. Patients were followed for up to 4.6 years (mean of 3.4 years).
1Assessed by a urinary albumin to creatinine ratio in 2 of 3 morning voids of greater than or equal to 300 mg/g.
2Male patients over 60 kg were only enrolled if serum creatinine was > 1.5 mg/dL (> 133 micromol/L).
The primary endpoint of the study was the composite endpoint of doubling of serum creatinine, end-stage renal disease (need for dialysis or transplantation), or death. For patients reaching the primary composite endpoint the results showed that treatment with Cozaar as compared with placebo resulted in a reduction in the relative risk of 16.1%. For the following individual and combined components of the primary endpoint, the results also showed significant risk reduction in the group treated with Cozaar a reduction in the relative risk of 25.3% in doubling of serum creatinine; a reduction in the relative risk of 28.6% in end-stage renal disease; a reduction in the relative risk of 19.9% in end-stage renal disease or death; a reduction in the relative risk of 21.0% in doubling serum creatinine or end-stage renal disease (see Table 4).
There was no significant difference observed in the rate of death among patients treated with Cozaar (21%) compared to those on placebo (20.3%). There was no significant difference observed in the incidence of cardiovascular mortality and morbidity between patients treated with Cozaar and those who received placebo (p=0.253).
The secondary endpoints of the study were: change in proteinuria; the rate of progression of renal disease; and the composite of morbidity and mortality from cardiovascular causes (hospitalisation for heart failure, myocardial infarction, revascularisation, stroke, hospitalisation for unstable angina, or cardiovascular death). The results showed an average reduction of 34.3% in the level of proteinuria in the group treated with Cozaar (p < 0.001). Treatment with Cozaar reduced the rate of decline in renal function during the chronic phase of the study by 13.9%, p=0.003 (median rate of decline of 18.5%, p=0.01) as measured by the reciprocal of the serum creatinine.
In this study, Cozaar was generally well tolerated as evidenced by a similar incidence of discontinuations due to side effects compared to placebo.
There was a significant reduction in the mean number of end stage renal disease [ESRD] days with Cozaar treatment over 3.5 years [33.6 less ESRD days with Cozaar treatment, (-56.3, -10.9, 95% Confidence Interval)]. It is estimated that one case of ESRD would be prevented for every 16 patients that are treated with Cozaar over a 3.5 year period.

5.2 Pharmacokinetic Properties

Absorption.

Following oral administration, losartan is well absorbed and undergoes first-pass metabolism, forming an active carboxylic acid metabolite and other inactive metabolites. The active carboxylic metabolite is responsible for most of the angiotensin II receptor antagonism.
The systemic bioavailability of losartan tablets is approximately 33%. Mean peak concentrations of losartan and its active metabolite are reached in 1 hour and in 3-4 hours, respectively. While maximum plasma concentrations of losartan and its active metabolite are approximately equal, the AUC of the metabolite is about 4 times as great as that of losartan. Food slows the absorption of losartan and leads to slightly decreased levels of losartan (AUC about 18% decreased) and the active metabolite (AUC about 13% decreased). However, in each case the changes were small and there was no clinically significant effect on the plasma concentration profile of losartan.

Distribution.

Both losartan and its active metabolite are > 99% bound to plasma proteins, primarily albumin. The volume of distribution of losartan is 34 litres. Studies in rats indicate that losartan crosses the blood-brain barrier poorly, if at all.
The volume of distribution of losartan is about 34 litres and of the active metabolite is about 12 litres.

Metabolism.

Losartan undergoes substantial first-pass metabolism by cytochrome P450.
About 14% of an intravenously- or orally-administered dose of losartan is converted to its active metabolite. Following oral and intravenous administration of 14C-labelled losartan potassium, circulating plasma radioactivity primarily is attributed to losartan and its active metabolite. In vitro studies indicate that cytochrome P450 2C9 and 3A4 are involved in the biotransformation of losartan to its metabolites. Minimal conversion of losartan to its active metabolite was seen in about one percent of individuals studied.
In addition to the active metabolite, inactive metabolites are formed, including two major metabolites formed by hydroxylation of the butyl side chain and a minor metabolite, an N-2 tetrazole glucuronide.

Elimination.

Plasma clearance of losartan and its active metabolite is about 600 mL/min and 50 mL/min, respectively. Renal clearance of losartan and its active metabolite is about 74 mL/min and 26 mL/min, respectively. When losartan is administered orally, about 4% of the dose is excreted unchanged in the urine, and about 6% of the dose is excreted in the urine as active metabolite. The pharmacokinetics of losartan and its active metabolite are linear with oral losartan potassium doses up to 200 mg.
Following oral administration, plasma concentrations of losartan and its active metabolites decline polyexponentially with a terminal half-life of about 2 hours and 6-9 hours, respectively. During once-daily dosing with 100 mg, neither losartan nor its active metabolite accumulates significantly in plasma.
Both biliary and urinary excretion contribute to the elimination of losartan and its metabolites. Following an oral dose of 14C-labelled losartan in man, about 35% of radioactivity is recovered in the urine and 58% in the faeces.

Characteristics in patients.

Plasma concentrations of losartan are not altered in patients with creatinine clearance above 30 mL/min. In patients with lower creatinine clearance, AUCs are about 50% greater and they are doubled in haemodialysis patients.
Plasma concentrations of the active metabolite are not significantly altered in patients with renal impairment or in haemodialysis patients. No dosage adjustment is necessary for patients with renal impairment unless they are volume depleted.
Following oral administration in patients with mild to moderate alcoholic cirrhosis of the liver, plasma concentrations of losartan and its active metabolite were, respectively, 5-fold and 1.7-fold greater than those seen in young male volunteers.
Neither losartan nor the active metabolite can be removed by haemodialysis.

5.3 Preclinical Safety Data

Genotoxicity.

No evidence of genotoxic activity was observed in assays for DNA damage, gene mutations and chromosomal damage.

Carcinogenicity.

In animal studies, there was no evidence of carcinogenic activity when losartan potassium was administered orally to mice at doses up to 200 mg/kg/day for 92 weeks, or to rats at doses up to 270 mg/kg/day for 105 weeks.

6 Pharmaceutical Particulars

6.1 List of Excipients

Each tablet of Cozaar contains the following inactive ingredients: microcrystalline cellulose, lactose monohydrate, pregelatinised maize starch, magnesium stearate, hyprolose, hypromellose, titanium dioxide and carnauba wax.
Cozaar 50 mg tablets contain 4.24 mg (0.108 mEq) of potassium.

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.

6.3 Shelf Life

The expiry date can be found on the packaging. In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG).

6.4 Special Precautions for Storage

Store at temperatures below 30°C.

6.5 Nature and Contents of Container

Available in a blister pack containing 30 tablets.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of by taking to your local pharmacy.

6.7 Physicochemical Properties

Losartan potassium, a non-peptide molecule, is chemically described as 2-butyl-4-chloro-1- [[2'-(1H-tetrazol-5-yl) [1,1'-biphenyl]-4-yl] methyl]-1H-imidazole-5-methanol monopotassium salt.
Its empirical formula is C22H22ClKN6O. It has a molecular weight of 461.01.
Oxidation of the 5-hydroxymethyl group on the imidazole ring results in the active metabolite of losartan.

Chemical structure.


CAS number.

The CAS Registry Number is 124750-99-8.

7 Medicine Schedule (Poisons Standard)

Prescription Only Medicine (Schedule 4).

Summary Table of Changes